Gijselinck Ilse, Engelborghs Sebastiaan, Maes Githa, Cuijt Ivy, Peeters Karin, Mattheijssens Maria, Joris Geert, Cras Patrick, Martin Jean-Jacques, De Deyn Peter P, Kumar-Singh Samir, Van Broeckhoven Christine, Cruts Marc
University of Antwerp, B-2610 Antwerp, Belgium.
Arch Neurol. 2010 May;67(5):606-16. doi: 10.1001/archneurol.2010.82.
Frontotemporal lobar degeneration (FTLD) is a neurodegenerative brain disorder that can be accompanied by signs of amyotrophic lateral sclerosis (ALS).
To identify a novel gene for FTLD-ALS.
Genome-wide linkage study in a multiplex family with FTLD-ALS with subsequent fine mapping and mutation analyses.
Memory Clinic of the Middelheim General Hospital.
An extended Belgian family with autosomal dominant FTLD-ALS, DR14, with a mean age at onset of 58.1 years (range, 51-65 years [n = 9]) and mean disease duration of 6.4 years (range, 1-17 years [n = 9]). The proband with clinical FTLD showed typical FTLD pathology with neuronal ubiquitin-immunoreactive inclusions that were positive for the transactivation response DNA-binding protein 43 (TDP-43).
Linkage to chromosome 9 and 14.
We found significant linkage to chromosome 9p23-q21 (multipoint logarithm of odds [LOD] score = 3.38) overlapping with a known FTLD-ALS locus (ALSFTD2) and nearly significant linkage to a second locus at chromosome 14q31-q32 (multipoint LOD score = 2.79). Obligate meiotic recombinants defined candidate regions of 74.7 megabase pairs (Mb) at chromosome 9 and 14.6 Mb near the telomere of chromosome 14q. In both loci, the disease haplotype segregated in all patients in the family. Mutation analysis of selected genes and copy number variation analysis in both loci did not reveal segregating pathogenic mutations.
Family DR14 provides additional significant evidence for the importance of the chromosome 9 gene to FTLD-ALS and reveals a possible novel locus for FTLD-ALS at chromosome 14. The identification of the underlying genetic defect(s) will significantly contribute to the understanding of neurodegenerative disease mechanisms in FTLD, ALS, and associated neurodegenerative disorders.
额颞叶变性（FTLD）是一种神经退行性脑部疾病，可伴有肌萎缩侧索硬化（ALS）的症状。
鉴定FTLD-ALS的一个新基因。
对一个患有FTLD-ALS的多重家庭进行全基因组连锁研究，随后进行精细定位和突变分析。
米德尔海姆综合医院记忆门诊。
一个比利时大家庭，患有常染色体显性FTLD-ALS（DR14），平均发病年龄为58.1岁（范围为51 - 65岁[n = 9]），平均病程为6.4年（范围为1 - 17年[n = 9]）。临床诊断为FTLD的先证者表现出典型的FTLD病理特征，神经元泛素免疫反应性包涵体对反式激活反应DNA结合蛋白43（TDP-43）呈阳性。
与9号和14号染色体的连锁。
我们发现与9号染色体p23 - q21区域存在显著连锁（多点对数优势[LOD]评分 = 3.38），该区域与一个已知的FTLD-ALS基因座（ALSFTD2）重叠，并且与14号染色体q31 - q32区域的第二个基因座存在近乎显著的连锁（多点LOD评分 = 2.79）。确定的减数分裂重组体定义了9号染色体上74.7兆碱基对（Mb）以及14号染色体q端粒附近14.6 Mb的候选区域。在这两个基因座中，疾病单倍型在家族中的所有患者中均呈分离状态。对选定基因的突变分析和两个基因座的拷贝数变异分析均未发现分离的致病突变。
DR14家族为9号染色体基因对FTLD-ALS的重要性提供了额外的重要证据，并揭示了14号染色体上一个可能的FTLD-ALS新基因座。潜在遗传缺陷的鉴定将极大地有助于理解FTLD、ALS及相关神经退行性疾病的神经退行性疾病机制。
